The section for the study of gastrointestinal tumors is divided into two broad areas that include the development of strategies for the treatment of gastrointestinal tumors and the development of therapies for the treatment of opportunistic infections in patients with AIDS. 'Me antineoplastic investigations revolve around the development of a complete understanding of the mechanisms of action and the mechanisms of resistance to the antimetabolite class of antineoplastic agents, specifically, 5-fluorouracil and methotrexate. The central focus of this area is to improve the therapy of gastrointestinal cancer by 1) modulating the activity of the available antimetabolite agents in an effort to improve activity and circumvent resistance mechanisms defined from both preclinical and clinical investigations 2) enhancing the dose intensity of antimetabolite agents through use of biologic agents such as interferon and colony stimulating factors and 3) investigating the activity and mechanisms of action of novel agents for efficacy in the treatment of gastrointestinal malignancy. In addition, we are investigating the autocrine growth factor requirements for colorectal carcinoma and adenoma cells in an attempt to characterize and interfere with these growth requirements using specific agents such as suramin. By investigating the progression from adenoma to carcinoma we hope to understand how various autocrine factors may be involved in malignant transformation with the ultimate goal of preventing such transformation. The investigations of therapies for opportunistic infections is focused on the interactions of antifolate agents on the metabolic pathways in toxoplasma gondii and pneuniocystis carinii . In addition to the use of basic biochemical technologies, we are using the tools of molecular biology to provide quantities of the critical enzymes for characterization and to aide in the search for new therapeutic agents.